Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Int J Mol Sci. 2024 May 29;25(11):5915. doi: 10.3390/ijms25115915.
Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.
胰岛素样生长因子（IGF）系统的失调决定了各种病理状况的发生，包括癌症。因此，已经开发出了治疗策略来阻断肿瘤细胞中的该系统，但临床试验的结果令人失望。经过几十年的研究，可以肯定的是，抗 IGF 靶向药物疗效不佳的主要原因之一源于对该轴分子复杂性的低估。遗传、转录、转录后和功能相互作用因子干扰了该轴的典型成分的活性，支持需要采用组合方法来有效阻断该系统。此外，癌细胞与来自细胞外区室的多种因素相互作用，这些因素强烈影响细胞命运。在这篇综述中，我们将介绍导致 IGF 系统失调的新型细胞外机制，以及这种危险联系对癌症标志和对已知和新型抗 IGF 药物的反应的影响。对细胞内和细胞外微环境的更深入了解可能为更好地解析癌症中 IGF 轴的复杂性提供新的动力，并为设计新的治疗方法提供新的线索。
